Gene therapy effective in animal studies of Parkinson's disease

An international team of scientists has reversed some of the effects of Parkinson's disease in rats with a drug-induced form of the progressive movement disorder.

By inserting corrective genes into the brain, researchers were able to trigger the regeneration of a critical bundle of nerve fibers. The new growth was linked to significant -- but not complete -- recovery of the animals' ability to use their paws spontaneously, said Ronald J. Mandel, a University of Florida scientist who was part of the team and a co-author of a recent Journal of Neuroscience article describing the research.

"For a long time, we had known that if the cells that produce the chemical dopamine died, then you would get the effects of Parkinson's disease.

Researchers therefore focused on trying to save those cells. But when we were able to do so, we still saw all the signs of the disease," said Mandel, an associate professor in the College of Medicine's neuroscience department who is affiliated with UF's Brain and Genetics institutes.

"What we've shown here is that you can get real functional recovery by instead targeting the treatment to the forebrain. There you can see a regrowth of the fibers or axons that are connected to the dopamine-producing cells. Without that connection, those cells are incapable of supporting normal movement," Mandel said.

Parkinson's disease has been in the news in recent months with the revelation that actor Michael J. Fox has the disorder, which is characterized by rigidity in the arms and legs, tremors and movement difficulties. Some of the symptoms can be alleviated with medications such as levodopa, a drug that converts to dopamine in the brain, but their effectiveness lessens over time. Surgery also can minimize some effects, but there is no cure for the gradually worsening condition, which afflicts an estimated 1.2 million people in the United States and Canada.

The gene therapy experiments were conducted at Lund University in Lund, Sweden, where Mandel was a visiting scientist before joining the UF faculty last year. In addition to Mandel, the scientists included internationally renowned Parkinson's expert Anders Björklund, a pioneer of the experimental treatment involving the transplantation of fetal cells into the brains of Parkinson's patients, and Deniz Kirik, a physician pursuing his doctoral degree in the laboratory.

The researchers inserted copies of a gene to produce a specific protein in the brains of laboratory rats. The protein, known as GDNF, participates in the normal development of dopamine cells and the fibers that connect them to another part of the brain -- the striatum in the forebrain.

In separate experimental groups, the corrective genes were placed either in the part of the brain where the dopamine neurons reside (the substantia nigra) or in the striatum. In a third group, they were inserted in both areas. The gene copies were carried into the cells by recombinant adeno-associated virus, or AAV, a vector that so far has not been linked to any adverse effects in human and animal studies.

Four weeks after inserting the genes, the researchers induced Parkinson's by injecting a drug to destroy the dopamine cells. But for some rats, the gene therapy treatment had offered some protection against the drug and spurred on recovery from the damage the drug did cause. To the researchers' surprise, only the rats that received the treatment exclusively in the striatum improved, Mandel said. The effects persisted through the six months of the experiment.

"We saw signs of recovery in eight of the 11 rats in this group," Mandel said. "While they did not improve on all of the motor skills tests we put them through, they did show normal use of their paws on three of the seven exercises.

"For example, in one test, rats were placed in a cylinder in which they could move about freely," Mandel said. "A normal rat wants to rear up, put its paws on the wall and walk around to try to search the environment. But when Parkinson's has been induced, instead of using each front paw equally, they use their weaker paw only 15 percent of time. But after our treatment, eight of the rats returned to using each front paw half the time."

Autopsies later showed that in this group of rats, the initially destroyed dopamine fibers had begun to regenerate, thereby providing the critical link between the substantia nigra and the striatal area of the forebrain, Mandel said.

Mandel is conducting further animal experiments at UF, which boasts a team of AAV experts who are working to improve its effectiveness as a gene therapy vector. (For the studies in Sweden, the California-based gene therapy company Cell Genesys supplied the AAV vector.) Mandel's goal is to test the therapy in people within the next several years.

Jeffrey H. Kordower, a Parkinson's researcher at Rush-Presbyterian-St. Luke's Medical Center in Chicago, noted that human clinical trials already have unsuccessfully tried other ways to deliver the GDNF protein into the brain.
"Dr. Mandel's work illustrates one novel means of delivering this factor in an animal model and also makes the very important finding that it needs to be delivered to a specific region of the brain -- the striatum -- and not other potentially important sites," said Kordower, a professor of neurological sciences and director of the Research Center for Brain Repair at Rush. "As gene therapy for Parkinson's moves toward clinical trials, this information will be critical for the safe and efficacious planning of these trials."